THOUSAND OAKS, Calif.,
Jan. 10, 2017 /PRNewswire/
-- Amgen (NASDAQ:AMGN) today announced the Journal of the
American Medical Association (JAMA) publication of
findings from three Phase 3 studies of Parsabiv™ (etelcalcetide),
an investigational intravenous calcimimetic agent in the U.S. The
studies evaluated Parsabiv in more than 1,700 adults with secondary
hyperparathyroidism (sHPT) on hemodialysis and showed that the drug
produced statistically significant and clinically meaningful
reductions in serum parathyroid hormone (PTH) levels, a key marker
of sHPT. sHPT is a chronic and serious condition that is often
progressive among patients with chronic kidney disease (CKD) and is
associated with significant clinical consequences.1
"sHPT is often a progressive condition in patients with advanced
chronic kidney disease, including those with kidney failure.
Despite the use of phosphate binders and calcitriol or active
vitamin D analogs, management of sHPT has been relatively poor in a
sizeable proportion of patients," said Glenn M. Chertow, M.D., professor of Medicine
and chief of the Division of Nephrology at Stanford University School of Medicine.
"Intravenous treatment with etelcalcetide could give healthcare
providers greater control over calcimimetic delivery, and provide
patients with sHPT on hemodialysis an additional treatment option,
lowering parathyroid hormone and improving other key laboratory
parameters."
In two parallel Phase 3 randomized placebo-controlled studies in
CKD patients with sHPT on hemodialysis, Parsabiv met the primary
endpoint and significantly reduced serum PTH by more than 30
percent in 74.7 percent of patients compared to 8.9 percent given
placebo. In addition, a head-to-head study comparing Parsabiv to
oral Sensipar® (cinacalcet) also met its primary
endpoint. This head-to-head study showed Parsabiv was non-inferior
to oral Sensipar in the proportion of patients achieving 30 percent
or greater serum PTH reduction. Further, Parsabiv was superior to
Sensipar for the secondary endpoints of proportion of patients
achieving greater than 30 percent and greater than 50
percent reduction in mean PTH during the Efficacy Assessment Phase
(EAP) compared with baseline.
A total of 1,706 patients were enrolled across the three trials
to evaluate the safety and efficacy of Parsabiv in the treatment of
adult sHPT patients on hemodialysis.
The two placebo-controlled trials were double-blind studies in a
total of 1,023 adult patients with sHPT on hemodialysis. The
patients were randomized to receive intravenous Parsabiv or placebo
three times a week at the end of their dialysis sessions, and both
arms also received standard of care as prescribed by the treating
physician. Both of the trials showed that, by weeks 20-27,
significantly more Parsabiv patients compared to placebo patients
achieved:
- Greater than a 30 percent reduction from baseline in mean serum
PTH during weeks 20-27: 74.0 percent versus 8.3 percent
(p<0.001) and 75.3 percent versus 9.6 percent
(p<0.001)
- Serum PTH levels of 300 pg/mL or less: 49.6 percent versus 5.1
percent (p<0.001) and 53.3 percent versus 4.6 percent
(p<0.001)
The most common treatment-emergent adverse events (TEAEs) in the
placebo-controlled studies that occurred at a rate greater than 10
percent in the Parsabiv group, and more frequently than in the
placebo group in either of the studies, were blood calcium
decreases (asymptomatic reductions in serum calcium), muscle
spasms, diarrhea, nausea and vomiting. The overall rates of fatal
adverse events, serious adverse events and adverse events leading
to discontinuation of investigational product were similar in the
Parsabiv and placebo groups.
The head-to-head study against Sensipar included 683 patients
with sHPT on hemodialysis, and found Parsabiv resulted in a higher
proportion of patients reaching at least a 30 percent reduction in
mean serum PTH during weeks 20-27 compared to baseline: 68.2
percent versus 57.7 percent, respectively (p=0.004).
Significantly more Parsabiv patients also achieved greater than a
50 percent reduction from baseline in mean serum PTH during weeks
20-27: 52.4 percent versus 40.2 percent, respectively
(p=0.001). There was no statistically significant difference
between the two groups in the mean number of days of vomiting or
nausea per week in the first eight weeks, a secondary endpoint.
TEAEs that were reported in greater than 10 percent of patients in
either arm included blood calcium decreases, nausea, vomiting and
diarrhea. TEAEs of hypocalcemia (symptomatic) were reported in 5.0
percent of patients who received Parsabiv versus 2.3 percent in the
Sensipar group.
"As we work toward advancing the treatment of patients with sHPT
on hemodialysis, the findings published in JAMA are
particularly noteworthy given patients were typically receiving
conventional therapy for sHPT, but showed a sustained reduction in
PTH over 26 weeks in the placebo controlled trials," said
Sean E. Harper, M.D., executive vice
president of Research and Development at Amgen. "We are encouraged
by these data as they demonstrate improvements in key biomarkers
for sHPT and support its potential for a disease that has not seen
any advances in more than a decade."
In the U.S., the Parsabiv application has been resubmitted to
the Food and Drug Administration (FDA) addressing the Complete
Response Letter. The U.S. user fee goal date is Feb. 9, 2017.
On Nov. 11, 2016, the European Commission (EC) granted marketing
authorization for Parsabiv for the treatment of sHPT in adult
patients with CKD on hemodialysis. Russian regulatory authorities
approved Parsabiv on Dec. 5, 2016. Regulatory submissions for
Parsabiv are currently pending in Colombia, Brazil, Switzerland and South Africa. On Dec. 19, 2016, Amgen's
collaborator, Ono Pharmaceuticals, received manufacturing and
marketing approval in Japan for
Parsabiv for the treatment of secondary hyperparathyroidism in
patients on hemodialysis.
About the Phase 3 Placebo-Controlled Studies
In the
two 26-week, multicenter, randomized, double-blind,
placebo-controlled studies, an aggregate of 1,023 adult patients
with sHPT (PTH greater than 400 pg/mL) on hemodialysis were
randomized to receive intravenous Parsabiv or placebo three times a
week at the end of their dialysis sessions. All patients,
regardless of treatment assignment, received standard of care with
phosphate binders and calcitriol or active vitamin D analogs, as
prescribed.
The primary endpoint of the studies was the proportion of
patients achieving greater than 30 percent reduction in PTH during
the EAP. Secondary endpoints included the proportion of patients
with PTH less than or equal to 300 pg/mL during the EAP, and
percent change from baseline during the EAP for PTH, serum calcium,
phosphate and calcium phosphate product (Ca x P).
About the Phase 3 Head-to-Head Study
The Phase 3
randomized, double-blind, double-dummy, active controlled trial was
designed to compare the efficacy and safety of intravenous Parsabiv
and oral Sensipar in 683 adult sHPT patients (340 randomized to
Parsabiv and 343 to Sensipar) on hemodialysis. The patients were
from 164 sites in the U.S., Canada, Europe, Russia and New
Zealand. Patients receiving maintenance hemodialysis three
times per week with sHPT (pre-dialysis serum PTH>500 pg/mL) on
stable doses of calcium supplements or phosphate binders and
calcitriol or active vitamin D analogs, if prescribed, with
albumin-corrected serum calcium >8.3 mg/dL were eligible for
participation.
Patients who were randomized to treatment with Parsabiv/oral
placebo received intravenous doses three times a week at the end of
their dialysis sessions and daily oral doses of placebo tablets.
Patients in the comparison group received daily oral doses of
Sensipar tablets and intravenous doses of placebo three times a
week at the end of their dialysis sessions. The primary endpoint
was the proportion of patients with greater than 30 percent
reduction from baseline in mean serum PTH during the EAP (weeks
20-27). Key secondary endpoints included the proportion of patients
with greater than 50 percent and greater than 30 percent reduction
in PTH, and the mean weekly days of self-reported nausea and
vomiting over the first eight weeks.
About Secondary Hyperparathyroidism
sHPT is a chronic
and serious condition which affects many of the approximately two
million people throughout the world who are receiving dialysis,
including 468,000 people in the U.S.1-3 Approximately 88
percent of dialysis patients and 79 percent of patients on
hemodialysis will develop sHPT.4 sHPT refers to the
excessive secretion of PTH by the parathyroid glands in response to
decreased renal function and impaired mineral
metabolism.1,5 The elevated levels of PTH can lead to an
increase in the release of calcium and phosphorus from the
bones.6 sHPT is often initially silent and
asymptomatic.1 As a result, sHPT is frequently
underdiagnosed and undertreated.1,7
About Parsabiv™ (etelcalcetide) in the U.S.
Parsabiv
is a novel calcimimetic agent in clinical development for the
treatment of sHPT in adult CKD patients on hemodialysis that is
administered intravenously at the end of the hemodialysis session.
A calcimimetic is a drug that mimics the action of calcium by
activating the calcium-sensing receptors on the parathyroid gland.
Parsabiv binds to and activates the calcium-sensing receptor on the
parathyroid gland, thereby decreasing PTH levels.
Parsabiv Indication and Important Safety Information in the
EU
Parsabiv is indicated for the treatment of secondary
hyperparathyroidism (sHPT) in adult patients with chronic kidney
disease (CKD) on hemodialysis therapy.
Contraindications: Hypersensitivity to the active
substance or to any of the excipients. Parsabiv should not be
initiated if corrected serum calcium is less than the lower limit
of the normal range.
Special Warnings and Precautions:
Hypocalcaemia:
Since Parsabiv lowers serum calcium, patients should be advised to
seek medical attention if they experience symptoms of hypocalcaemia
and should be monitored for the occurrence of
hypocalcaemia. Serum calcium levels should be measured prior
to initiating treatment, within 1 week of initiation or dose
adjustment of Parsabiv and every 4 weeks during treatment.
Potential manifestations of hypocalcaemia include paraesthesias,
myalgias, muscle spasm and seizures. Decreases in serum
calcium can prolong the QT interval, potentially resulting in
ventricular arrhythmia. The threshold for seizures may be
lowered by significant reductions in serum calcium levels.
Worsening heart failure: Decreased myocardial performance,
hypotension, and congestive heart failure may be associated with
significant reductions in serum calcium levels.
Co-administration with other medicinal products
Administer Parsabiv with caution in patients receiving any other
medicinal products known to lower serum calcium. Patients receiving
Parsabiv should not be given cinacalcet. Concurrent administration
may result in severe hypocalcaemia.
Interactions: No interaction studies have been performed.
There is no known risk of pharmacokinetic interaction with
Parsabiv.
Fertility, Pregnancy and Lactation: There are no or
limited amount of data from the use of Parsabiv in pregnant women.
Animal studies do not indicate direct or indirect harmful effects
with respect to reproductive toxicity. As a precautionary measure,
it is preferable to avoid the use of Parsabiv during pregnancy. A
risk to breastfed newborns/infants cannot be excluded. A decision
must be made whether to discontinue breast-feeding or
discontinue/abstain from Parsabiv therapy taking into account the
benefit of breast-feeding for the child and the benefit of therapy
for the woman. No data are available on the effect of Parsabiv on
human fertility. Animal studies do not indicate direct or indirect
harmful effects with respect to fertility.
Undesirable Effects: The following common (≥10%) adverse
reactions have been reported in pivotal, controlled clinical
studies: decreases in serum calcium, diarrhea, nausea, vomiting,
and muscle spasms.
Pharmaceutical Precautions: Store in a refrigerator (2
degrees C – 8 degrees C). Once removed from the
refrigerator, Parsabiv must be used within 7 days if stored in the
original carton.
To see the full Parsabiv Safety Information, visit
http://www.ema.europa.eu.
About Sensipar® (cinacalcet) in the U.S.
Sensipar® (cinacalcet) is the first oral calcimimetic
agent approved by the U.S. Food and Drug Administration (FDA) for
the treatment of sHPT in adult patients with CKD on dialysis.
Sensipar is not indicated for use in adult patients with CKD who
are not on dialysis because of an increased risk of hypocalcemia.
The therapy is also approved in the U.S. for treatment of
hypercalcemia in adult patients with parathyroid carcinoma and
hypercalcemia in adult patients with primary hyperparathyrodisim
(HPT) for whom parathyroidectomy would be indicated on the basis of
serum calcium levels, but who are unable to undergo
parathyroidectomy. Sensipar binds to the calcium-sensing receptor,
resulting in a drop in PTH levels by inhibiting PTH synthesis and
secretion. In addition, the reductions in PTH lower serum calcium
and phosphorus levels.
Sensipar Important Safety Information in the
U.S.
Sensipar® (cinacalcet) treatment
initiation is contraindicated if serum calcium is less than the
lower limit of the normal range (8.4 mg/dL).
Sensipar® lowers serum calcium; therefore, it is
important that patients are carefully monitored for the occurrence
of hypocalcemia. Life threatening events and fatal outcomes
associated with hypocalcemia have been reported in patients treated
with Sensipar®, including pediatric patients. Decreases
in serum calcium can prolong the QT interval, potentially resulting
in ventricular arrhythmia. Cases of QT prolongation and ventricular
arrhythmia secondary to hypocalcemia have been reported in patients
treated with Sensipar®.
Significant reductions in calcium may lower the threshold for
seizures. Patients, particularly those with a history of seizure
disorder, should be carefully monitored for the occurrence of low
serum calcium or symptoms of hypocalcemia.
In Sensipar® postmarketing use, isolated,
idiosyncratic cases of hypotension, worsening heart failure, and/or
arrhythmia were reported in patients with impaired cardiac
function. The causal relationship to
Sensipar® therapy could not be completely excluded
and may be mediated by reductions in serum calcium levels.
Adynamic bone disease may develop if intact parathyroid hormone
(iPTH) levels are suppressed below 100 pg/mL. Patients with
moderate to severe hepatic impairment should be monitored
throughout treatment with Sensipar®, as cinacalcet
exposure assessed by area under the curve (AUC) was higher than in
patients with normal hepatic function.
Patients with secondary HPT: Serum calcium and serum phosphorus
should be measured within 1 week and PTH should be measured 1 to 4
weeks after initiation or dose adjustment of Sensipar®.
Once the maintenance dose has been established, serum calcium and
serum phosphorus should be measured approximately monthly, and PTH
every 1 to 3 months. Patients with primary HPT or parathyroid
carcinoma: Serum calcium should be measured within 1 week after
initiation or dose adjustment of Sensipar®. Once
maintenance dose levels have been established, serum calcium should
be measured every 2 months.
In clinical trials of patients with secondary HPT comparing
Sensipar® to placebo, the most commonly reported
side effects were nausea (31 percent vs. 19 percent), vomiting (27
percent vs. 15 percent), and diarrhea (21 percent vs. 20 percent).
In clinical trials of patients with primary HPT and parathyroid
carcinoma treated with Sensipar®, the most commonly
reported side effects were nausea (63 percent), vomiting (46
percent), and paresthesia (20 percent).
Please see Full Prescribing Information.
About Mimpara® (cinacalcet) in the
EU
Mimpara® (cinacalcet) is the first oral
calcimimetic agent approved by the European Medicines Agency for
the treatment of sHPT in patients with CKD on dialysis. The therapy
is also approved in the EU for the treatment of hypercalcemia in
patients with parathyroid carcinoma and hypercalcemia in adult
patients with primary HPT for whom parathyroidectomy would be
indicated on the basis of serum calcium levels (as defined by
relevant treatment guidelines), but in whom parathyroidectomy is
not clinically appropriate or is contraindicated. Mimpara binds to
the calcium-sensing receptor, resulting in a drop in PTH levels by
inhibiting PTH synthesis and secretion. In addition, the reductions
in PTH lower serum calcium and phosphorus levels.
Mimpara Important Safety Information in the
EU
Contraindications: Hypersensitivity to the active
substance or to any of the excipients
Special Warnings and Precautions:
Serum Calcium:
Mimpara treatment should not be initiated in patients with a
serum calcium below the lower limit of the normal range. Life
threatening events and fatal outcomes associated with hypocalcaemia
have been reported in adult and paediatric patients treated with
Mimpara. Manifestations of hypocalcaemia may include paraesthesias,
myalgias, cramping, tetany and convulsions. Decreases in serum
calcium can also prolong the QT interval, potentially resulting in
ventricular arrhythmia secondary to hypocalcaemia. The threshold
for seizures is lowered by significant reductions in serum calcium
levels. Patients should be monitored carefully for the occurrence
of hypocalcaemia. Serum calcium should be measured within 1 week
after initiation or dose adjustment of Mimpara. Once the
maintenance dose has been established, serum calcium should be
measured approximately monthly.
Hypotension and/or worsening heart failure: In post-marketing
safety surveillance, isolated, idiosyncratic cases of hypotension
and/or worsening heart failure have been reported in patients with
impaired cardiac function, in which a causal relationship to
cinacalcet could not be completely excluded and may be mediated by
reductions in serum calcium levels.
Hepatic impairment:
Due to the potential for 2 to 4 fold higher plasma levels of
cinacalcet in patients with moderate to severe hepatic impairment,
Mimpara should be used with caution in these patients and treatment
should be closely monitored.
In the treatment of secondary hyperparathyroidism the most
commonly reported adverse reactions in clinical trials were nausea
and vomiting.
To see the full Mimpara Safety Information, visit
http://www.ema.europa.eu.
About Amgen
Amgen is committed to unlocking the
potential of biology for patients suffering from serious illnesses
by discovering, developing, manufacturing and delivering innovative
human therapeutics. This approach begins by using tools like
advanced human genetics to unravel the complexities of disease and
understand the fundamentals of human biology.
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its expertise to strive for solutions that improve health outcomes
and dramatically improve people's lives. A biotechnology pioneer
since 1980, Amgen has grown to be one of the world's leading
independent biotechnology companies, has reached millions of
patients around the world and is developing a pipeline of medicines
with breakaway potential.
For more information, visit www.amgen.com and follow us on
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3 National Kidney Foundation. Fast Facts. Available
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https://www.kidney.org/news/newsroom/factsheets/FastFacts Accessed
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4 Data on File, Amgen; 2016.
5 Joy MS, Karagiannis PC, Peyerl FW. Outcomes of
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6 National Institutes of Health. MedlinePlus:
Hyperparathyroidism. Available at:
www.nlm.nih.gov/medlineplus/ency/article/001215.htm Accessed
November 28, 2016.
7 National Kidney Foundation. Parathyroid Hormone and
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https://www.kidney.org/sites/default/files/02-10-4899_GB_SHPT-PTH_v8.pdf
Accessed November 28, 2016.
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